Abstract
Acute myeloid leukemia (AML) is a heterogeneous disorder among hematologic malignancies. Several genetic alterations occur in this disease, which cause proliferative progression, reducing differentiation and apoptosis in leukemic cells as well as increasing their survival. In the genetic study of AML, genetic translocations, gene overexpression, and mutations effective upon biology and pathogenesis of this disease have been recognized. Proto-oncogenes and tumor suppressor genes, which are important in normal development of myeloid cells, are involved in the regulation of cell cycle and apoptosis, undergo mutation in this type of leukemia, and are effective in prognosis of AML subtypes. This review deals with these genes, the assessment of which can be important in the diagnosis and prognosis of patients as well as therapeutic outcome.
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Introduction
Acute myeloid leukemia (AML) is developed due to somatically acquired genetic alterations in hematopoietic cells [1]. Genetic changes in AML result in proliferative progression as well as reducing leukemic cell differentiation and apoptosis [2]. Excessive proliferation of stem or progenitor cells causes replacement of normal erythroid, myeloid, and megakaryocytic precursors with malignant cells, which gives rise to hematopoietic deficiency (i.e., granulocytopenia, thrombocytopenia, or anemia) in the bone marrow (BM) and peripheral blood [3, 4]. Approximately 20,000 patients were diagnosed with AML with over 10,000 death cases of AML patients in the USA in 2015 [5]. AML is more frequently seen in the elderly. The incidence of AML in the USA is 3.5 cases per 100,000 people, being higher in patients >65 years compared with younger patients (15.9 vs 1.7 cases, respectively) [6].
Mutations in this disease can be divided into two categories: (1) mutation in the genes involved in cell proliferation and survival such as mutations of FLT3, oncogenic Ras, PTPN11, and TEL/PDGFbR gene fusions and (2) mutations affecting differentiation and apoptosis, such as AML/ETO and PML/RARa fusions, MLL rearrangements, mutations in CEBPA, CBF, HOX family members, CBP/P300, and coactivators of TIF1 [7].
Proto-oncogenes and tumor suppressor genes encode the proteins involved in the regulation of cell surface receptors for cytokines, growth factors, signal transduction molecules, transcription factors, as well as epigenetic regulators and regulators of cell cycle and apoptosis [3]. Typically, most of these genes are involved in normal development of myeloid cell, so any disruption in their expression or loss of their normal function leads to leukemogenesis [8]. For example, Flt3 (the receptor tyrosine kinase) is expressed in early hematopoietic progenitor cells and plays important roles in proliferation and survival [9]. This receptor shows significant functions associated with c-kit and stem cell factor receptor. In cooperation with lineage-specific cytokines, Flt3 activation increases colony-forming capacity of all hematopoietic lineages [10]. Furthermore, several gene mutations were found to cause epigenetic changes and to deregulate gene expression in AML, such as mutations of the TET2 gene as well as IDH1 and DNMT3A mutations [11].
Studies show that approximately 35 % of AML patients have several translocations causing oncofusion proteins. Transcription of these proteins could target mechanisms such as transcription, epigenetics, cell structure, and nuclear receptors as well as causing uncontrolled proliferation of progenitor cells [12]. There are four important translocations in AML with a frequency of 3–10 %, including PML-RARa, AML1-ETO, CBFb-MYH11, and MLL-fusions as well as other oncofusion proteins with a lower incidence [13]. For example, t(15; 17) together with fusion of RARA (retinoic acid receptor alpha) gene with a previously unknown gene designated as PML (promyelocytic leukemia) encodes an oncofusion protein effective in the regulation of apoptosis and prevention of cell differentiation [14]. Another common translocation in AML is t(8;21) (q22;q22), which gives rise to acute myeloid gene 1 (AML1) and ETO (eight twenty-one) [15]. The AML1 gene encodes a critical transcription factor that regulates a variety of genes involved in proliferation and differentiation of many cell types, including those within the hematopoietic system [16]. On the other hand, ETO is a protein-harboring transcriptional repressor activities. Consequently, AML1-ETO functions as a transcriptional repressor [17].
Various cytogenetic aberrations occur in AML, which are very important for the prognosis of patients and predict the possibility of response to treatment or relapse in patients [11]. These are divided to three groups: (1) favorable risk: t(8; 21) (q22; q22), inv [16] (p13q22)/t(16; 16) (p13; q22), or t(15; 17) (q22; q21); (2) intermediate risk: normal cytogenetics, +8, t(9; 11); and (3) unfavorable risk: −7, inv [3] (q21q26)/t(3; 3) (q21; q26), balanced translocations involving 11q23 other than t(9; 11) (p22; q23) or complex karyotype [18, 19]. Delaunay et al. studied 110 patients with inv [16]/t(16; 16) AML with a complete remission (CR) rate of 93 % [20]. Clozel et al. have introduced the association of this type of AML with an overall good prognosis; however, relapse still occurs in 30–35 % of patients and with a higher frequency in older patients [21]. In addition, adverse prognostic factors include increasing age, a poor performance before treatment, unfavorable cytogenetic abnormalities, and a high white blood cell count. Also, therapy-related AML or AML with a myelodysplastic or myeloproliferative syndrome history is more resistant to usual treatments than de novo AML [11].
Molecular and cytological studies show that genetic mutations in AML patients are the most important prognostic factors for predicting clinical outcome of patients [1]. Therefore, these changes may be used as diagnostic and prognostic markers. In this article, we have attempted to introduce the prognostic role of oncogenes and tumor suppressor genes in AML cells.
Oncogenes in AML
Mutations in proto-oncogenes lead to excessive proliferation of myeloid cells in leukemia [22]. Some oncogenes encode hematopoietic growth factors or growth factor receptors like FLT3, and some others regulate cell proliferation or differentiation (e.g., RAS). Mutation, translocation, and amplification in these important cell processes contribute to leukemogenesis [23, 24]. Abnormalities in cellular oncogenes have been reported in leukemia, and the most important reported AML oncogenes are herewith evaluated (Table 1). Given the importance of these genes in the diagnosis of disease, they can contribute to monitoring of disease and determination of prognosis as MRD markers [25].
Mutation in FMS-like tyrosine kinase 3 (FLT3) receptor gene, which encodes a membrane protein of type III platelet-derived growth factor (PDGF) family, is an important mutation in AML. FLT3 binding to its ligand and its subsequent activation induces cell proliferation and survival [18, 26]. In addition, this protein plays a role in hematopoiesis and malignant transformation of primitive hematopoietic cells [27, 28]. Mutation in this gene occurs in about 30 % of AML cases in two forms: internal tandem duplication (ITD) and tyrosine kinase domain (TKD). It occurs as a result of duplication and insertion of juxta membrane domain sequence with ≈20–30 % incidence in AML patients and following missense point mutation within the activation loop of the second TKD with lower incidence, respectively [29–31]. The high prevalence of FLT3-ITDs in AML patients raises it as a common marker detectable by PCR [32]. Studies have shown that FLT3-ITD detection is associated with increased BM blasts and white blood cell (WBC) count in peripheral blood; therefore, the death rate and relapse risk is increased, which is a sign of poor outcome in normal karyotype AML (NK-AML) [33]. If this mutation is detected in AML cases, inhibition of its downstream pathways, including AKT, BAD, BCL2, and STAT5[18] can help improve the specific treatment process via suppression of this gene, which may be used to evaluate the prognosis of patients, especially in cases with normal karyotype.
AML1 (CBFA2/PEBP2αB/RUNX1) is another gene undergoing mutation in acute leukemias (Table 1) [34]. The encoded AML1 protein combined with a common heterodimeric binding cofactor (CBFβ) is attached to a specific DNA sequence TGT/cGGT and regulates the expression of genes effective upon hematopoiesis, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and colony-stimulating factor 1 (CSF1) receptor [35]. This protein is an important regulator of progenitor cell fate and marks the proliferation, differentiation, and apoptosis pathways in the cell [36]. This gene is involved in both normal and malignant hematopoiesis. In leukemia, this subunit undergoes t(8; 21), t(3; 21), and t(16; 21) translocation. AML1/ETO t(8; 21) (q22; q22) fusion is observed in nearly 10–15 % of AML cases. This fusion inhibits the proliferation and differentiation of hematopoietic cells and increases self-renewal of hematopoietic stem cells [37]. Assessment of AML1 mutations in de novo AML is associated with male sex, older age, immature FAB subtypes, and trisomy 8, which are associated with poor prognosis during treatment [38].
SALL4 is another oncogene involved in AML, which belongs to the four-member family of SALL1 to SALL4. SALL protein is among C2H2 zinc finger transcription factors [39]. This gene family is involved in normal hematopoiesis and development of cells [40]. SALL4 isoform has been reported in many hematologic malignancies, including AML, precursor B cell lymphoblastic leukemia/lymphoma, and myelodysplastic syndrome (MDS) [41, 42]. SALL4 directly regulates the expression of apoptotic genes such as TP53, BCL2, TNF, and PTEN, indicating its role in leukemogenesis [43]. Investigation of NB4 leukemic cell line (M3) indicated that the apoptosis pathway was induced in cells with a low expression level of this gene and caused cell cycle arrest [44]. Reduction of SALL4 level causes overexpression of SALL4 downstream target protein of Bmi-1 and maintains the apoptosis capacity of the cell. These epigenetic alterations in the methylation of SALL4 gene promoter are able to induce apoptosis in the cells [43, 45]. SALL4 is differently expressed in various subgroups of AML, causing acquisition and maintenance of blastic traits such as self-renewal and/or lack of differentiation in leukemic stem cells (LSCs), which is associated with older age and increased WBC count of patients [46, 47]. Increased expression of SALL4 in AML patients leads to a worse prognosis via induction of drug resistance [48]. Therefore, according to the regulatory role of this gene in leukemic cell survival, downregulation of SALL4 can significantly induce cell apoptosis, and the importance of evaluating the expression level of SALL4 as a new method to predict prognosis and response to treatment in patients is thus highlighted.
Given the foregoing, prognostic significance of oncogenes in AML is understood, which can be used as markers for monitoring diagnosis and monitoring of patients.
Tumor suppressor genes in AML
Tumor suppressor genes encode proteins with inhibitory roles in the cell cycle. Loss-of-function mutations in these genes cause uncontrolled proliferation of cells and promotion of malignancy [49]. Tumor suppressor genes are generally known as negative regulators of cell growth effective upon invasive and metastatic ability [50]. In this section, a number of important tumor suppressor genes mutated in AML will be discussed.
WT1 transcription factor is important in cell growth and development with different expression levels in various stages of cell development. For example, it is expressed during embryonic development in the urogenital system and is expressed in adult urogenital system, central nervous system, and hematopoietic tissues like BM and lymph nodes [51]. WT1 has a low expression level in CD34+ cells in normal human BM and acts as a tumor suppressor gene [52]. When a deletion occurs in the second zinc finger of this protein, its expression is increased in early human BM cells, which results in growth arrest and reduced colony formation [53, 54]. WT1 is expressed in several leukemia types and can be evaluated to detect residual disease. WT1 mutations have been reported with different frequencies in heterozygous, homozygous, and compound heterozygous forms in several adult and childhood AML cases [55]. These mutations have been detected in cytogenetically normal AML or in combination with other mutations such as FLT3 [56, 57]. Mutation in WT1 may even be detected during relapse in patients who do not show it upon diagnosis [58]. Higher levels of this protein are associated with decreased attainment of remission, poor disease-free survival, and/or poor overall survival [59] (Table 2).
The promyelocytic leukemia (PML) gene (15q22) is a tumor suppressor gene present in normal cells as nuclear structures called PML-nuclear bodies (PML-NBs) [60][50]. Cell cycle regulation, viral infections, growth inhibition, tumor suppression, apoptosis, and transcriptional regulation are among the intracellular functions of these PML-NBs, which are involved in the acetylation of P53 tumor suppressor and regulation of the oncogenic function of Ras [61, 62]. PML-4 (isoform IV) has a more prominent tumor suppressor role and can efficiently inhibit the transcription of anti-apoptotic proteins such as survivin as well as apoptosis signaling by binding to regulators of apoptotic genes like histone deacetylases (HDAC) [63–65]. This gene is fused with retinoic acid receptor alpha (RARα) gene in acute promyelocytic leukemia (APL) sub-group and encodes the t(15; 17) oncofusion protein [63], which is detected in 97 % of APL patients. The protein resulting from this translocation inhibits differentiation of myeloid hematopoietic cells via suppression of PU.1 [66, 67]. In general, the presence of this fusion protein causes good prognosis in the patient. PML-RARA fusion can be used for both diagnosis and detection of minimal residual disease [68]. Measurement of PML/RARα fusion gene is important to predict relapse even in the absence of t(15; 17) by karyotyping and fluorescent in situ hybridization (Table 2).
Tet oncogene family member 2 (TET2) is mutated in a variety of hematologic disorders such as MDS, myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML), and AML, which has been reported secondarily in AML with a history of MDS/MPN [69, 70]. Mutations in this gene are usually observed in the form of deletion or uniparental disomy [71], increasing the self-renewal capacity of LSCs and causing defective hematopoiesis, monocytosis, and extramedullary hematopoiesis [72]. TET2 mutations are associated with older patients, higher WBC and blast counts, low platelet count, normal karyotype, intermediate-risk cytogenetics, as well as mutation in NPM1 and ASXL1 but exclusively with IDH mutation. Studies show that mutation in TET2 is developed due to IDH mutation as an epigenetic factor in AML [73–75]. TET2 gene has been associated with poor prognosis in AML patients but is considered as a good prognostic factor in MDS patients with trisomy 8 [76]. The difference in the relationship between this molecule with other molecules mutated in AML and various diseases indicates the prognostic value of this marker. TET1 is another family member of TET reported in t(10; 11) (q22; q23) translocation in some AML cases, which is developed due to fusion between TET1 and MLL in 11q23 position and belongs to acute myelomonocytic leukemia (FAB. M5) subgroup [77]. Therefore, according to the above, diagnostic and prognostic importance of tumor suppressor genes in AML patients is understood, which can pave the way for faster and more specific detection in each of the AML subtypes (Table 2).
Discussion and future perspective
AML is developed due to accumulation of abnormal blast cells in the BM, increased proliferation, and self-renewal which leads to hematopoietic insufficiency [4, 78]. So far, over 200 disorders have been reported in AML patients, which are cytogenetic findings important in the prognosis of patients (Fig. 1) [4]. In general, the factors affecting prognosis include age, initial leukocyte count, karyotype, immune phenotype, and response to remission-induction therapy. If the patient is older, has a higher WBC count, and does not respond to treatment, an adverse prognosis is expected for them [79, 80]. Mutations in AML patients are important for the diagnosis and prognosis of AML patients and are specifically introduced for each AML subtype. These molecular markers can also be used to monitor and evaluate patient’s CR rate, relapse risk (RR), and overall survival (OS) [81].
Given the role of oncogenes in the proliferation, differentiation, apoptosis, and survival of hematopoietic progenitors, they can give rise to several cancers such as leukemia if they are subject to mutation. Oncogene mutation with varied frequency is observed in AML subgroups. Considering Table 1, prognosis is poor in case of the presence of these genes even in favorable risk AML subgroup, including mutations in KIT [82].
Mutation of tumor suppressor genes in addition to factors such as patient’s age, translocations, and the involved cell line can be important markers for assessing the prognosis of patients. As can be seen in Table 2, mutation in these genes causes a poor prognosis; however, if mutation is detected in C/EBPα transcription factor, which is common in favorable risk disease group, a better prognosis is expected even in older patients [83]. Moreover, some of these genes are associated with patients’ age, for example, mutation in TET2 and IDH1 has not been reported in childhood AML [75, 84]. Thus, general understanding of molecular mechanisms responsible for leukemia would help design more specific diagnostic methods, better monitoring of disease prognosis, and treatment protocol.
In the past, cytogenetic factors were used as the most important prognostic factors to assess response to treatment and survival of patients. Today, a large number of molecular markers have been identified for molecular risk classification of AML. As a result, many reported results from studies need to be assessed and confirmed with more samples to introduce the most reliable available markers.
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Acknowledgments
This paper forms part of Maria Kavianpour’s M.Sc. thesis. We extend special thanks to Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran (Grant Number Th94/7), for the financial support. We appreciate the contribution of all our colleagues in the Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy.
Authors’ contributions
Najmaldin Saki conceived the manuscript and revised it. Maria Kavianpour, Ahmad Ahmad Zadeh, and Saeid Shahrabi wrote the manuscript and prepared the tables and figure.
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Highlights
Detection of oncogene or tumor suppressor gene mutations has been proposed for consideration of AML prognosis.
All oncogenes and tumor suppressor gene mutations cause poor prognosis in AML patients except for C/EBPα.
Oncogene or tumor suppressor gene mutations can be used as potential MRD markers.
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Kavianpour, M., Ahmadzadeh, A., Shahrabi, S. et al. Significance of oncogenes and tumor suppressor genes in AML prognosis. Tumor Biol. 37, 10041–10052 (2016). https://doi.org/10.1007/s13277-016-5067-1
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DOI: https://doi.org/10.1007/s13277-016-5067-1